Stable perindopril amlodipine tablet and preparation method thereof

Abstract

The invention relates to the technical field of pharmaceutical preparations, in particular to a stable perindopril amlodipine tablet and a preparation method thereof, and the tablet comprises the following components in percentage by weight: 5.0% of arginine perindopril; 3.5% of amlodipine besylate; 20%-40% of pregelatinized starch; 40%-68% of a microcrystalline cellulose colloidal silicon dioxide compound; 2.5%-6% of a disintegrating agent, wherein the disintegrating agent is selected from one or more of ion exchange resin, sodium alginate and croscarmellose sodium; the pregelatinized starch and the microcrystalline cellulose colloidal silicon dioxide compound are selected as main diluents, so that the Maillard reaction possibly occurring between the lactose and the active pharmaceutical ingredients is completely avoided, the problem of increase of related substances is fundamentally solved, and the stability and the safety of the product are remarkably improved.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical formulation technology, specifically to a stable perindopril amlodipine tablet and its preparation method. Background Technology

[0002] Perindopril-Amlodipine tablets, originally developed by Servier (France) and marketed under the brand name Kaisuda®, are a combination formulation of arginine perindopril and amlodipine besylate. Arginine perindopril is a third-generation angiotensin-converting enzyme inhibitor (ACEI) with the longest half-life. Its active metabolite, perindopril, reduces angiotensin production, dilates blood vessels, and lowers blood pressure, with a half-life of 17 hours. Amlodipine is a calcium channel blocker with the longest half-life among dihydropyridine calcium channel blockers. It lowers blood pressure by relaxing vascular smooth muscle, with a half-life of 35-50 hours. Currently, this product is mainly used clinically to treat hypertension, suitable for patients whose blood pressure cannot be satisfactorily controlled by amlodipine or perindopril alone, or as an alternative therapy for patients taking both amlodipine and perindopril simultaneously. Arginine perindopril and amlodipine besylate represent a combination of CCB and ACEI, with complementary mechanisms that enhance antihypertensive efficacy while reducing adverse reactions. In terms of duration of action, the two are a powerful combination, providing a longer-lasting effect in controlling blood pressure than olmesartan medoxomil and amlodipine tablets.

[0003] Patent CN202210240042.7 describes a technical solution to improve the stratification of active ingredients during tableting by adding a portion of fine-particle lactose during the mixing stage. However, this solution has the following obvious drawbacks: First, there is a compatibility risk between the raw material amlodipine besylate and the lactose in the formulation, which is prone to Maillard degradation reaction leading to the growth of related substances; second, the product disintegration time is too long, posing safety and efficacy risks; third, fine-particle lactose (200 mesh) has extremely poor flowability, which will reduce the overall flowability of the product formulation, resulting in unstable loading during high-speed tableting production, leading to large differences in tablet weight and limiting tableting production efficiency; in addition, lactose (T80) is granular lactose, and its density and flowability differ significantly from the other materials in the formulation. In large-scale (batch size > 1 million tablets) continuous powder tableting process, the active ingredients will still experience stratification, limiting the scale of industrialization.

[0004] Therefore, there is an urgent need to develop a stable and efficient perindopril amlodipine tablet and its preparation method to solve the above-mentioned technical problems. Summary of the Invention

[0005] The purpose of this invention is to overcome the above-mentioned defects in the prior art and provide a stable perindopril amlodipine tablet and its preparation method. This method can effectively avoid the risk of related substances growth caused by Maillard reaction in the product. The dry granulation process improves the flowability of the powder, making the active ingredient and excipients better combined. It significantly improves the problems of content stratification and tablet weight difference in the high-speed tableting process during large-scale industrial production.

[0006] To achieve the above objectives, the present invention provides the following technical solution: A stable perindopril amlodipine tablet comprises the following components in weight percentage: Arginine perindopril 5.0%; Amlodipine besylate 3.5%; Pregelatinized starch 20%-40%; Microcrystalline cellulose colloidal silica composite 40%-68%; The disintegrant is 2.5%-6%, and the disintegrant is selected from one or more of ion exchange resin, sodium alginate, and croscarmellose sodium; 1% magnesium stearate.

[0007] Preferably, the disintegrant is sodium alginate.

[0008] Preferably, the disintegrant is croscarmellose sodium.

[0009] Preferably, the disintegrant is an ion exchange resin.

[0010] The present invention also provides a method for preparing the above-mentioned tablets, comprising the following steps: (1) First, arginine perindopril, amlodipine besylate and a portion of microcrystalline cellulose colloidal silica complex were premixed in equal increments to obtain a premix; (2) Next, add internal additives to the premix, including pregelatinized starch, microcrystalline cellulose colloidal silica complex and disintegrant, and mix them together after passing through a 40-mesh sway sieve twice for 20-30 minutes. (3) Then, add magnesium stearate and mix for 5-10 minutes; (4) Next, dry granulation is performed to obtain qualified granules, of which the proportion of granules with a diameter of 40 mesh or above is not less than 30%; (5) Next, add the excipients and mix for 10 min-20 min, wherein the excipients include microcrystalline cellulose colloidal silica complex and disintegrant; (6) Finally, add magnesium stearate, mix well, and compress into tablets to obtain the finished product.

[0011] In one embodiment of the present invention, the equal-incremental premixing method in step (1) is as follows: arginine perindopril and amlodipine besylate are first mixed with a small amount of microcrystalline cellulose colloidal silica complex, and then the remaining microcrystalline cellulose colloidal silica complex is gradually added and mixed. This special premixing method can significantly improve the binding degree between the active ingredient and the excipients, effectively avoiding the stratification phenomenon during the tableting process.

[0012] Preferably, the mixing time in step (2) is 25 minutes. Experiments have verified that this time ensures uniform mixing of materials without causing over-mixing and stratification.

[0013] Preferably, the dry granulation in step (4) uses a pressure of 8-12 MPa and a granulation screen aperture of 30 mesh. More preferably, the dry granulation pressure is 10 MPa, under which the granules have the best flowability and compressibility.

[0014] Preferably, the mixing time in step (5) is 15 minutes. This time period is sufficient to ensure that the added excipients and granules are fully mixed without causing material separation.

[0015] The beneficial effects of this invention are: 1. By selecting a pregelatinized starch and microcrystalline cellulose colloidal silica complex as the main diluent, this invention completely avoids the Maillard reaction that may occur between lactose and the active pharmaceutical ingredient, fundamentally solving the problem of related substance growth and significantly improving the stability and safety of the product.

[0016] 2. This invention employs a dry granulation process, in which no water is involved, thus avoiding the adverse effects of moisture introduced by wet granulation on the stability of arginine perindopril. At the same time, the granulation process significantly improves the flowability of the powder, effectively solving the problem of tablet weight variation during high-speed tableting.

[0017] 3. This invention innovatively adopts an equal-incremental premixing method and a segmented addition strategy of excipients, which greatly improves the degree of binding between active ingredients and excipients and effectively solves the content stratification problem in large-scale industrial production.

[0018] 4. This invention, through systematic screening of disintegrants and optimization of their addition amount, controls the product disintegration time to within 3 minutes, significantly improving the bioavailability and clinical efficacy of the drug.

[0019] In summary, the perindopril amlodipine tablets and their preparation method provided by this invention not only solve the problems of Maillard reaction risk, large tablet weight difference, content stratification and long disintegration time in the prior art, but also have strong process compliance, stable and controllable product quality, extended shelf life, and improved product safety and efficacy. Attached Figure Description

[0020] Figure 1 This is a process flow diagram of the method for preparing perindopril amlodipine tablets according to the present invention. Detailed Implementation

[0021] The present invention will be further described in detail below with reference to specific embodiments, but the scope of protection of the present invention is not limited to the following embodiments.

[0022] This invention, through in-depth research, reveals that the stability issues in perindopril-amlodipine tablets mainly stem from two aspects: First, both arginine perindopril and amlodipine besylate contain primary amino groups in their structures, which readily undergo Maillard reactions with reducing sugars such as lactose, leading to the growth of related substances. Second, arginine perindopril has strong hygroscopic properties, easily absorbing moisture during the production process and during finished product storage, resulting in decreased tablet hardness, accelerated disintegration, and the growth of related substances. To address these issues, this invention uses a pregelatinized starch and microcrystalline cellulose colloidal silica complex to completely replace lactose as a diluent. Simultaneously, through dry granulation and an equal-volume incremental mixing method, it effectively solves problems such as poor powder flowability and content stratification. The microcrystalline cellulose colloidal silica complex (SMCC) is a novel pharmaceutical excipient obtained by spray drying microcrystalline cellulose and microcrystalline silica powder (CSD) in a 98:2 ratio, and is commercially available.

[0023] In the technical solution of this invention, the microcrystalline cellulose colloidal silica complex not only acts as a diluent but also functions as an internal desiccant, effectively resisting the hygroscopicity of arginine perindopril. This excipient possesses high flowability, high dispersibility, good hygroscopic resistance, and compressibility, and is widely used in oral pharmaceutical preparations and food. It is a relatively non-toxic and non-irritating substance. Pregelatinized starch, as a modified starch, is commonly used in tablets as a binder, diluent, and disintegrant, and also has a self-lubricating effect, significantly improving powder flowability and granulation.

[0024] In selecting disintegrants, the present invention conducted a systematic screening and found that crospovidone had poor compatibility with the formulation, and sodium carboxymethyl starch had poor compressibility and process compliance. Sodium alginate, ion exchange resin, and crospovidone carboxymethyl cellulose were more suitable for this formulation. In particular, sodium alginate has a very high hydration swelling tendency when in contact with water, and does not form clumps during disintegration, which helps the drug dissolve rapidly.

[0025] In addition, the present invention has optimized the particle size of the active ingredients, controlling the particle size of arginine perindopril raw material within the D50 range (10-60 μm) and the particle size of amlodipine besylate within the D50 range (10-30 μm). This helps to improve the mixing and binding degree of the raw materials with the microcrystalline cellulose colloidal silica complex, significantly improve the content stratification, and accelerate drug release to improve efficacy.

[0026] The present invention will be further described below through specific embodiments. Example

[0027] This embodiment provides a stable perindopril amlodipine tablet with the following component ratio (weight percentage): arginine perindopril 5.0%, amlodipine besylate 3.5%, pregelatinized starch 31.0%, microcrystalline cellulose colloidal silica complex 55.5% (45.5% internally added and 10.0% externally added), sodium alginate 4.0% (2.5% internally added and 1.5% externally added), and magnesium stearate 1.0% (0.5% internally added and 0.5% externally added).

[0028] The preparation method includes the following steps: (1) First, 10 mg of arginine perindopril and 6.935 mg of amlodipine besylate were premixed with a small amount of 17 mg of microcrystalline cellulose colloidal silica complex in equal increments to obtain a premix (batch percentage 17%). (2) Next, add the internal additives (62mg of pregelatinized starch, 74mg of microcrystalline cellulose colloidal silica complex, and 5mg of sodium alginate) to the above premix and pass them through a 40-mesh sway sieve twice and mix for 25 minutes. (3) Then, add 1 mg of magnesium stearate, the lubricant added to the internal portion, and continue mixing for 8 min; (4) Next, dry granulation is used at a pressure of 10 MPa and a granulation screen with a mesh size of 30 mesh. The qualified granules obtained are collected, and the proportion of granules with a diameter of 40 mesh or larger is not less than 30%. (5) Next, add the excipients (20 mg of microcrystalline cellulose colloidal silica complex and 3 mg of sodium alginate) and mix for 15 min; (6) Finally, add 1 mg of magnesium stearate as an external lubricant, mix for 8 min, and compress to obtain the finished product (plain tablets). Example

[0029] This embodiment provides a stable perindopril amlodipine tablet with the following component ratio (weight percentage): arginine perindopril 5.0%, amlodipine besylate 3.5%, pregelatinized starch 21.0%, microcrystalline cellulose colloidal silica complex 67.5% (52.5% internal and 15.0% external), sodium alginate 2.5% (1.5% internal and 1.0% external), and magnesium stearate 1.0% (0.5% internal and 0.5% external).

[0030] The preparation method includes the following steps: (1) First, 10 mg of arginine perindopril and 6.935 mg of amlodipine besylate were premixed with a small amount of 17 mg of microcrystalline cellulose colloidal silica complex in equal increments to obtain a premix (batch percentage 17%). (2) Next, add the internal additives (41 mg of pregelatinized starch, 88 mg of microcrystalline cellulose colloidal silica complex, and 3 mg of sodium alginate) to the above premix and pass them through a 40-mesh sway sieve twice and mix for 20 min. (3) Then, add 1 mg of magnesium stearate, the lubricant added internally, and continue mixing for 5 min; (4) Next, dry granulation is used at a pressure of 8 MPa and a granulation screen with a mesh size of 30 mesh. The qualified granules obtained are collected, and the proportion of granules with a diameter of 40 mesh or larger is not less than 35%. (5) Next, add the excipients (30 mg of microcrystalline cellulose colloidal silica complex and 2 mg of sodium alginate) and mix for 10 min; (6) Finally, add 1 mg of magnesium stearate as an external lubricant, mix for 5 min, and compress to obtain the finished product (plain tablets). Example

[0031] This embodiment provides a stable perindopril amlodipine tablet with the following component ratio (weight percentage): arginine perindopril 5.0%, amlodipine besylate 3.5%, pregelatinized starch 40.0%, microcrystalline cellulose colloidal silica complex 44.5% (34.5% internally added and 10.0% externally added), sodium alginate 6.0% (4.0% internally added and 2.0% externally added), and magnesium stearate 1.0% (0.5% internally added and 0.5% externally added).

[0032] The preparation method includes the following steps: (1) First, 10 mg of arginine perindopril and 6.935 mg of amlodipine besylate were premixed with a small amount of 17 mg of microcrystalline cellulose colloidal silica complex in equal increments to obtain a premix (batch percentage 17%). (2) Next, add the internal additives (80mg of pregelatinized starch, 52mg of microcrystalline cellulose colloidal silica complex, and 8mg of sodium alginate) to the above premix and pass them through a 40-mesh sway sieve twice and mix for 30 minutes. (3) Then, add 1 mg of magnesium stearate, the lubricant added to the internal portion, and continue mixing for 10 min; (4) Next, dry granulation is used at a pressure of 12 MPa and a granulation screen with a mesh size of 30 mesh. The qualified granules obtained are collected, and the proportion of granules with a diameter of 40 mesh or larger is not less than 40%. (5) Next, add the excipients (20 mg of microcrystalline cellulose colloidal silica complex and 4 mg of sodium alginate) and mix for 20 min; (6) Finally, add 1 mg of magnesium stearate as an external lubricant, mix for 10 min, and compress to obtain the finished product (plain tablets). Example

[0033] This embodiment provides a stable perindopril amlodipine tablet with the following component ratio (weight percentage): arginine perindopril 5.0%, amlodipine besylate 3.5%, pregelatinized starch 30.0%, microcrystalline cellulose colloidal silica complex 55.5% (45.5% internal and 10.0% external), croscarmellose sodium 5.0% (2.5% internal and 2.5% external), and magnesium stearate 1.0% (0.5% internal and 0.5% external).

[0034] The preparation method is similar to that in Example 1, except that sodium croscarmellose is used instead of sodium alginate as the disintegrant. The specific steps are as follows: (1) First, 10 mg of arginine perindopril and 6.935 mg of amlodipine besylate were premixed with a small amount of 17 mg of microcrystalline cellulose colloidal silica complex in equal increments to obtain a premix (batch percentage 17%). (2) Next, add the internal additives (60mg of pregelatinized starch, 74mg of microcrystalline cellulose colloidal silica complex, and 5mg of cross-linked carboxymethyl cellulose sodium) to the above premix and pass them through a 40-mesh swirl sieve twice and mix for 25 minutes. (3) Then, add 1 mg of magnesium stearate, the lubricant added to the internal portion, and continue mixing for 8 min; (4) Next, dry granulation is used at a pressure of 10 MPa and a granulation screen with a mesh size of 30 mesh. The qualified granules obtained are collected, and the proportion of granules with a diameter of 40 mesh or larger is not less than 32%. (5) Next, add the excipients (20 mg of microcrystalline cellulose colloidal silica complex and 5 mg of cross-linked sodium carboxymethyl cellulose) and mix for 15 min; (6) Finally, add 1 mg of magnesium stearate as an external lubricant, mix for 8 min, and compress to obtain the finished product (plain tablets). Example

[0035] This embodiment provides a stable perindopril amlodipine tablet with the following component ratio (weight percentage): arginine perindopril 5.0%, amlodipine besylate 3.5%, pregelatinized starch 30.0%, microcrystalline cellulose colloidal silica complex 55.5% (45.5% internal and 10.0% external), ion exchange resin 5.0% (2.5% internal and 2.5% external), and magnesium stearate 1.0% (0.5% internal and 0.5% external).

[0036] The preparation method is similar to that in Example 1, except that an ion exchange resin is used instead of sodium alginate as the disintegrant. The specific steps are as follows: (1) First, 10 mg of arginine perindopril and 6.935 mg of amlodipine besylate were premixed with a small amount of 17 mg of microcrystalline cellulose colloidal silica complex in equal increments to obtain a premix (batch percentage 17%). (2) Next, add the internal additives (60mg of pregelatinized starch, 74mg of microcrystalline cellulose colloidal silica complex, and 5mg of ion exchange resin) to the above premix and pass them through a 40-mesh sway sieve twice and mix for 25 minutes. (3) Then, add 1 mg of magnesium stearate, the lubricant added to the internal portion, and continue mixing for 8 min; (4) Next, dry granulation is used at a pressure of 10 MPa and a granulation screen with a mesh size of 30 mesh. The qualified granules obtained are collected, and the proportion of granules with a diameter of 40 mesh or larger is not less than 32%. (5) Next, add the excipients (20 mg of microcrystalline cellulose colloidal silica complex and 5 mg of ion exchange resin) and mix for 15 min; (6) Finally, add 1 mg of magnesium stearate as an external lubricant, mix for 8 min, and compress to obtain the finished product (plain tablets).

[0037] To verify the effectiveness and superiority of the technical solution of this invention, the following comparative examples were designed: Comparative Example 1 This comparative example uses lactose instead of pregelatinized starch and microcrystalline cellulose colloidal silica complex as the main diluent. The component ratio (weight percentage) is as follows: arginine perindopril 5.0%, amlodipine besylate 3.5%, lactose (T80) 56.0%, lactose (200 mesh) 30.0%, sodium alginate 4.5%, and magnesium stearate 1.0%.

[0038] The preparation method adopts a direct powder compression process: (1) Mix arginine perindopril, amlodipine besylate and a small amount of lactose (T80); (2) Add the remaining lactose (T80), lactose (200 mesh) and sodium alginate, and mix for 30 minutes; (3) Add magnesium stearate and mix for 5 minutes; (4) The finished product is obtained by direct compression.

[0039] Comparative Example 2 This comparative example uses the formulation of the present invention, but instead of a dry granulation process, a wet granulation process is used. The component ratio (weight percentage) is: arginine perindopril 5.0%, amlodipine besylate 3.5%, pregelatinized starch 30.0%, microcrystalline cellulose colloidal silica complex 55.5%, sodium alginate 5.0%, and magnesium stearate 1.0%.

[0040] The preparation method employs a wet granulation process: (1) Arginine perindopril, amlodipine besylate and partially pregelatinized starch and microcrystalline cellulose colloidal silica complex were mixed; (2) Add 80% ethanol as a binder to make a soft material; (3) Granulate the soft material through a 20-mesh sieve; (4) Dry the wet granules at 60°C until the moisture content does not exceed 2%; (5) Mix the dried granules with the remaining excipients; (6) Add magnesium stearate, mix and compress to obtain the finished product.

[0041] Comparative Example 3 This comparative example uses the formulation of the present invention, but instead of using an equal-incremental premixing method, all powders are mixed at once. The component ratio (weight percentage) is: arginine perindopril 5.0%, amlodipine besylate 3.5%, pregelatinized starch 30.0%, microcrystalline cellulose colloidal silica complex 55.5%, sodium alginate 5.0%, and magnesium stearate 1.0%.

[0042] Preparation method: (1) Mix arginine perindopril, amlodipine besylate and all pregelatinized starch, microcrystalline cellulose colloidal silica complex and sodium alginate together for 30 min at one time; (2) Add magnesium stearate and mix for 5 minutes; (3) Dry granulation is carried out at a pressure of 10 MPa and a granulation screen with a mesh size of 30 mesh. (4) Compress the tablets to obtain the finished product.

[0043] Comparative Example 4 This comparative example uses the formulation of the present invention, but instead of employing the strategy of adding excipients in stages (internal and external), all excipients are added at once before dry granulation. The component ratio (weight percentage) is: arginine perindopril 5.0%, amlodipine besylate 3.5%, pregelatinized starch 30.0%, microcrystalline cellulose colloidal silica complex 55.5%, sodium alginate 5.0%, and magnesium stearate 1.0%.

[0044] Preparation method: (1) Arginine perindopril, amlodipine besylate and a portion of microcrystalline cellulose colloidal silica complex were premixed in equal increments; (2) Add all remaining excipients (pregelatinized starch, microcrystalline cellulose colloidal silica complex, sodium alginate) and mix for 30 min; (3) Add all magnesium stearate and mix for 5 minutes; (4) Dry granulation is carried out at a pressure of 10 MPa and a granulation screen with a mesh size of 30 mesh. (5) Compress the tablets to obtain the finished product.

[0045] To evaluate the effectiveness of the technical solution of this invention, systematic tests were conducted on the above embodiments and comparative examples. The main test items included substances related to the high-temperature (60°C) test, uniformity of content controlled during single-dose tableting, tablet weight variation, and disintegration time. The test methods are as follows: 1. Related substances for high-temperature (60℃) tests: Samples (without packaging) were placed in a 60℃ incubator and analyzed by high-performance liquid chromatography (HPLC) at 0, 10, and 30 days. The determination method was performed according to General Chapter 0512 of the 2020 edition of the Chinese Pharmacopoeia, Part IV. For the test solution, 10 tablets of this product were placed in a 100ml volumetric flask, and an appropriate amount of acetonitrile-water (40:60) was added. The mixture was sonicated for 10 minutes to dissolve the main component. The solution was then diluted to the mark with acetonitrile-water (40:60), shaken well, filtered, and the filtrate was used as the test solution. For the reference solution, appropriate amounts of arginine perindopril and amlodipine besylate reference standards were accurately weighed, dissolved in acetonitrile-water (40:60), and diluted to prepare a solution containing 10μg of arginine perindopril and 5μg of amlodipine per ml. This solution was used as the reference solution.

[0046] 2. Controlling the content uniformity of a single dose during tablet compression: The assay was performed at at least 20 sampling points during the early (0-25 minutes), middle (50-100 minutes), and late (150-300 minutes) stages of tablet compression, using high-performance liquid chromatography (HPLC). The assay method was performed in accordance with General Chapter 0512 of Part IV of the 2020 edition of the Chinese Pharmacopoeia.

[0047] 3. Tablet weight differences: During the tableting process, 10 tablets were sampled every 15 minutes to weigh each tablet and calculate the tablet weight difference.

[0048] 4. Disintegration time: The disintegration time should be tested according to the General Chapters, Part IV, of the 2020 edition of the Chinese Pharmacopoeia. Based on the drug's in vivo absorption characteristics, it should disintegrate completely within 3 minutes.

[0049] The test results are as follows: Table 1. Results of determination of related substances in the high temperature (60℃) test (%) Sample number 0 days 10 days 30 days Example 1 0.32 0.45 0.78 Example 2 0.35 0.52 0.85 Example 3 0.38 0.57 0.92 Example 4 0.34 0.48 0.83 Example 5 0.36 0.51 0.87 Comparative Example 1 0.42 0.98 2.87 Comparative Example 2 0.39 0.76 1.52 Comparative Example 3 0.36 0.62 1.23 Comparative Example 4 0.35 0.59 1.18 Table 2. Content uniformity (RSD%) during single-dose tableting process Sample number Early stage Mid-term Later Full process Example 1 1.25 1.38 1.42 1.52 Example 2 1.32 1.45 1.53 1.68 Example 3 1.18 1.29 1.35 1.43 Example 4 1.28 1.4 1.46 1.58 Example 5 1.3 1.42 1.49 1.62 Comparative Example 1 2.35 3.28 4.75 5.32 Comparative Example 2 1.85 2.42 3.15 3.58 Comparative Example 3 2.15 2.68 3.42 3.89 Comparative Example 4 1.92 2.53 3.27 3.65 Table 3. Results of tablet weight variation test (RSD%) Sample number Difference in tablet weight Example 1 1.12 Example 2 1.25 Example 3 1.08 Example 4 1.15 Example 5 1.18 Comparative Example 1 3.85 Comparative Example 2 2.32 Comparative Example 3 2.75 Comparative Example 4 2.48 Table 4. Disintegration time test results (min) Sample number Disintegration Time Example 1 1.8 Example 2 2.2 Example 3 1.5 Example 4 2 Example 5 1.9 Comparative Example 1 4.5 Comparative Example 2 3.8 Comparative Example 3 3.2 Comparative Example 4 2.9 The test results above show that: 1. Related substances in high-temperature (60℃) test: After 30 days, the content of related substances in Examples 1-5 of this invention was controlled below 1.0%, far lower than the 2.87% in Comparative Example 1. This fully demonstrates that by avoiding the use of lactose as a diluent, this invention effectively prevents the growth of related substances caused by the Maillard reaction, significantly improving the stability of the product. In particular, Comparative Example 1, which used lactose as a diluent, showed the most significant growth in related substances, which is directly related to the Maillard reaction between the primary amino groups in the structures of arginine perindopril and amlodipine besylate and lactose.

[0050] 2. Content Uniformity Controlled in Single-Dose Tableting Process: The RSD values ​​of content uniformity throughout the entire process in Examples 1-5 of this invention were all controlled below 2.0%, while the RSD values ​​of Comparative Examples 1-4 were all above 3.5%. This indicates that the equal-incremental premixing method and the segmented addition of excipients strategy adopted in this invention significantly improved the binding degree between the active ingredient and the excipients, effectively solving the content stratification problem in large-scale industrial production. In particular, the content uniformity of Comparative Examples 1 and 3 was the worst, which is directly related to the failure to adopt the equal-incremental premixing method.

[0051] 3. Tablet Weight Variation: The RSD values ​​of tablet weight variation in Examples 1-5 of this invention were all controlled below 1.3%, while the RSD values ​​of Comparative Examples 1-4 were all above 2.3%. This indicates that the dry granulation process and the internal and external segmented addition of excipients adopted in this invention significantly improved the flowability of the powder and effectively solved the problem of tablet weight variation during high-speed tableting. In particular, Comparative Example 1, which used fine-particle-size lactose (200 mesh) with poor flowability, showed the largest tablet weight variation, which is completely consistent with the aforementioned analysis.

[0052] 4. Disintegration Time: The disintegration time of Examples 1-5 of this invention was controlled within 3 minutes, meeting the expected requirements. In contrast, the disintegration time of Comparative Examples 1-4 all exceeded 2.9 minutes, with Comparative Example 1 exhibiting a disintegration time as high as 4.5 minutes. This indicates that this invention, through systematic screening of disintegrants and optimization of their dosage, significantly improves the disintegration performance of the product, which is beneficial for enhancing drug bioavailability and clinical efficacy.

[0053] A comprehensive analysis of the above test results shows that Examples 1-5 of the present invention are significantly superior to Comparative Examples 1-4 in key indicators such as high-temperature test related substances, content uniformity, tablet weight difference, and disintegration time, fully demonstrating the effectiveness and superiority of the technical solution of the present invention. Among them, Example 1 performs the best and can be regarded as the optimal implementation scheme of the present invention.

[0054] The present invention achieves the above-mentioned technical effects through the following technical means: 1. By gaining a deep understanding of the molecular structure characteristics of arginine perindopril and amlodipine besylate, especially the Maillard reaction mechanism that may occur between primary amino groups and reducing sugars, a pregelatinized starch and microcrystalline cellulose colloidal silica complex was chosen to completely replace lactose as a diluent, thus fundamentally avoiding the growth of related substances caused by the Maillard reaction.

[0055] 2. By recognizing the hygroscopic properties of arginine perindopril, a microcrystalline cellulose colloidal silica complex with good hygroscopic resistance was selected as the main diluent, which also served as an internal desiccant, effectively controlling the moisture content of the product and improving its stability.

[0056] 3. By employing a dry granulation process, the moisture that may be introduced during wet granulation is avoided, and the entire process is water-free, which is especially important for formulations containing hygroscopic substances. At the same time, the dry granulation process significantly improves the flowability of the powder and effectively solves the problem of tablet weight variation during high-speed tableting.

[0057] 4. By innovatively adopting an equal-incremental premixing method and a segmented addition strategy of excipients, the binding degree between active ingredients and excipients is significantly improved, effectively solving the content stratification problem in large-scale industrial production. The key to this strategy is: first, to fully mix low-content active ingredients with some excipients to improve their dispersibility; and then to add excipients in segments before and after dry granulation to ensure the flowability and compressibility of the granules.

[0058] 5. By systematically screening disintegrants and optimizing their dosage, the most suitable combination of disintegrants for this formulation was selected, which controlled the product disintegration time to within 3 minutes, significantly improving the bioavailability and clinical efficacy of the drug.

[0059] In summary, the perindopril amlodipine tablets and their preparation method provided by this invention, through a series of innovative technical means, successfully solve the problems existing in the prior art, such as Maillard reaction risk, large tablet weight difference, content stratification, and long disintegration time. It has significant advantages such as strong process compliance, stable and controllable product quality, and long shelf life, providing an efficient and reliable technical solution for the industrial production of perindopril amlodipine compound preparations.

Claims

1. A stable perindopril-amlodipine tablet, characterized in that, The tablet comprises the following components by weight percentage: Arginine perindopril 5.0%; Amlodipine besylate 3.5%; Pregelatinized starch 20%-40%; Microcrystalline cellulose colloidal silica composite 40%-68%; The disintegrant is 2.5%-6%, and the disintegrant is selected from one or more of ion exchange resin, sodium alginate, and croscarmellose sodium; 1% magnesium stearate.

2. The tablet according to claim 1, characterized in that, The disintegrant is sodium alginate.

3. The tablet according to claim 1, characterized in that, The disintegrant is croscarmellose sodium.

4. The tablet according to claim 1, characterized in that, The disintegrant is an ion exchange resin.

5. A method for preparing a stable perindopril-amlodipine tablet as described in any one of claims 1-4, characterized in that, Includes the following steps: (1) First, arginine perindopril, amlodipine besylate and a portion of microcrystalline cellulose colloidal silica complex were premixed in equal increments to obtain a premix; (2) Next, add internal additives to the premix, including pregelatinized starch, microcrystalline cellulose colloidal silica complex and disintegrant, and mix them together after passing through a 40-mesh sway sieve twice for 20-30 minutes. (3) Then, add magnesium stearate and mix for 5-10 minutes; (4) Next, dry granulation is performed to obtain qualified granules, of which the proportion of granules with a diameter of 40 mesh or above is not less than 30%; (5) Next, add the excipients and mix for 10 min-20 min, wherein the excipients include microcrystalline cellulose colloidal silica complex and disintegrant; (6) Finally, add magnesium stearate, mix well, and compress into tablets to obtain the finished product.

6. The preparation method according to claim 5, characterized in that, The equal-incremental premixing method described in step (1) is as follows: first mix arginine perindopril and amlodipine besylate with a small amount of microcrystalline cellulose colloidal silica complex, and then gradually add the remaining microcrystalline cellulose colloidal silica complex for mixing.

7. The preparation method according to claim 5, characterized in that, The mixing time in step (2) is 25 min.

8. The preparation method according to claim 5, characterized in that, The dry granulation method described in step (4) uses a pressure of 8-12 MPa and a granulation screen aperture of 30 mesh.

9. The preparation method according to claim 8, characterized in that, The dry granulation pressure in step (4) is 10 MPa.

10. The preparation method according to claim 5, characterized in that, The mixing time in step (5) is 15 min.

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